Clinical Development of ABX464, drug candidate for HIV Functional Cure. Chief Medical Officer ABIVAX

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1 Clinical Development of ABX464, drug candidate for HIV Functional Cure Jean-Marc Steens, MD Chief Medical Officer ABIVAX 1

2 DECLARATION OF CONFLICT OF INTEREST GSK ABIVAX 2

3 ABX464: Mechanism of Action ABX464 is a first-in-class orally available antiviral small molecule that blocks HIV replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm 3 Campos Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis. Retrovirology Apr 9

4 HIV RNA (copies/ml) ABX464 shows long-lasting viral load reduction vs. HAART in tg mice Preclinical efficacy data in a transgenic (humanized) mouse model* Treatment HAART Triple therapy ABX464 - Monotherapy Treatment HAART HAART With ABX464, HIV viral titres remain low compared to existing therapies ABX464 ABX464 p=0.005 p= These data suggest control of HIV by the immune system *adapted from: Campos et al., Retrovirology 2015, 12:30 4

5 ABX464:Mechanism of Action Molecular target: CBC 80/20 Activity: Conformational change of CBC Complex Enhanced RNA splicing Biological effects: Enhanced viral RNA splicing and Prevention of REV mediated export of long viral RNA Hypotheses being investigated: 1. Generation of neoantigens and inititiation of immune response 2. Cytotoxicity for reservoir cells by peptides related to viral RNA 3. Generation of deficient virus 1. Enhanced splicing of a long, noncoding RNA, leading to mir124 upregulation 2. Cytokine modulation Outcome: HIV: Reduction of viral load HIV: Sustained biological control of viral load HIV and other inflammatory diseases : Dampening of inflammation Observed outcome: In vitro In vivo Note: Italic characters = hypotheses 5

6 ABX464 Mechanism of action 6

7 ABX464 Mechanism of Action The findings substantiate a mechanism of action for ABX464 that starts with CBC 80/20 binding and enhancement of mrna splicing which leads to the following : Viral load reduction and elimination of HIV from the latent reservoir through immune response to putative new peptides generated by viral RNA splicing A negligible effect of ABX464 on cellular splicing ABX464 upregulates the anti-inflammatory mir-124, caused by splicing of long non-coding RNA ( Inc RNA ) 7

8 ABX464 Clinical Profile ABX464 has ABX464 acceptable HIV safety what profile, do we patient know exposure? > 180 patients ABX464 has antiviral properties ( study 003 ) Two independent studies showed that reduction of HIV DNA in blood from HIV well suppressed patients is feasible ( study 004 / 005 ) Single copy assay showed reduction in residual viremia Mir124 is being overexpressed in tissue Phase IIB is being planned in US / EU based on these data, supported by investigators and SAB 8 8

9 ABX : Study Scheme Vandekerckhove et al, ABX464 Decreases Total HIV DNA and Integrated HIV DNA in PBMCs When Administered During 28 Days to HIV-infected Virologically Suppressed Patients. EACS October

10 Mean HIV DNA Change (copies/mio PBMCs) Total HIV PBMC DNA Change: Day (SD 119) n=4 67 (SD 104) n=4 n=7 n= SD, standard deviation Placebo ABX464 Non-responders -186 (SD 114) ABX464 Responders ABX464 Responders Vandekerckhove et al, ABX464 Decreases Total HIV DNA and Integrated HIV DNA in PBMCs When Administered During 28 Days to HIV-infected Virologically Suppressed Patients EACS October

11 ABX Study Title: An Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of ABX464 in HIV-1 Seronegative and Seropositive Adults Primary objective: To evaluate the distribution of ABX464 and its main metabolite (N-Glu) in various compartments in HIV-1 Seronegative and Seropositive adult subjects Secondary objectives: To evaluate the safety of ABX464 administered once daily at one dose, alone in HIVuninfected subjects and in combination with ARTs in HIV-1 infected adult subjects; To evaluate the effect of ABX464 on the HIV reservoir cells in HIV-infected adult subjects; To evaluate the effect of ABX464 on the control of the viral load and the CD4+/CD8+ in HIV-infected adult subjects 11

12 ABX : Cohort 1 COHORT 1 (N=12) HIV-infected subjects VL<50 copies/ml Current CD4 > 600 cells/mm 3 CD4 nadir > 250 cells/mm 3 Post primary VL 100,000 copies/ml Over 12 months Rx with DTG or RAL plus TDF/FTC or ABC/FTC Screening (V1) Baseline (V 2) End of Rx (V 3) ABX mg orally daily for 28 days F/Up (V 4) End of Rx + 28 days (V5) Tissue sampling Day 0 Day 28 Day 56 12

13 ABX-005: Sampling Peripheral blood Systemic safety haematology renal hepatic PK (up to 8h post dose) Peripheral CD4+ T cell purification HIV DNA HIV RNA Plasma viremia Rectal tissue PK MMC HIV DNA HIV RNA Flow cytometry Proteome Transcriptome Rectal secretions Microbiome 13

14 ABX : Baseline Demographics 11 male participants were recruited Age: Mean 45.0 (median 48.0, range 29-55) years Ethnicity: 11 white Nadir CD4: Mean 515 (median 501, range cells/mm 3 ) CD4 T cells: Mean 911 (median 812, range cells/mm 3 ) 14

15 ABX : Safety No SAEs No grade 3 or higher AEs 59 Grade 1 or 2 AEs, (45 (76.3%) related, 14 (23.7%) unrelated) 2 withdrawals due to AEs (Related) - G1 abdominal pain, hyperlipasemia, headache, and G2 hyperamylasemia - G1 headache, myalgia, asthenia, insomnia, and backache 1 temporary discontinuation due to AE (Related) - G1 headache Most common AEs (>30%) - nausea, myalgia, back pain, headache 15

16 HIV DNA copies per million CD4+ T cells HIV-DNA cp/10 6 CD4 + T cells Ratio to BaseLine ABX : HIV DNA HIV-DNA reservoir in CD4+ T cells from PBMCs at Baseline and Day 28 P= d0 d d0 d28 16

17 HIV RNA copies / ml ABX : Residual Plasma HIV Viremia by SCA All participants had <50 copies of HIV RNA at study enrollment 6 LOQ = 0.5 HIV RNA copies/ml 4 Residual viremia was detected in 5 participants 2 In 4 participants there was a decrease between d0 and d28; one participant did not attend for d28 0 sampling d0 9/9 patients either decreased (n=4) or maintained Time (days) their residual pvl suppressed from d0 to d28 Increase 0/9 Decrease 4/9 Stable 5/9 8 n = 9 d28 17

18 Over expression threshold cycle (C t ) ABX : mirna-124 mirna124 is an anti-inflammatory microrna -6,0-7,0 All participants (n=7) had over-expression of -8,0-9,0 mirna124 in rectal biopsies -10,0-11,0 Mean ratio between d0 and d28: * -12,0 ABX D0 D28 D56-6,0-8,0-10,0-12,0-14,0-6,0-7,0-8,0-9,0-10,0-11,0-12,0 ABX ABX ABX ,0 D0 D28 D56 D0 WD28 D56 D0 D28 D56-7,0-8,0-9,0-10,0-11,0-12,0 ABX ABX ,0 D0 D28 D56 D0 D28 D56-7,0-8,0-9,0-10,0-11,0-12,0-6,0-7,0-8,0-9,0-10,0-11,0-5,0-7,0-9,0-11,0-13,0-15,0-17,0 * Estimation based on the quantity of the target DNA template (amplicon) doubles every cycle. ABX D0 D28 D56 18

19 ABX : Conclusions Dosing was associated with adverse events that led to discontinuation of 2 study participants. All symptoms and biochemical abnormalities normalized upon drug withdrawal. There were no SAEs Exposure to 150 mg of ABX464 for 28 days was associated with a significant decrease in HIV-1 DNA in CD4+ T cells from baseline A decrease in residual plasma viremia was measured at D28 in some patients who still had residual plasma viremia at d0. CD4 T cell counts were stable MicroRNA 124 was over expressed at d28 versus d0 Overall, these data confirm the decrease in PBMC HIV-1 DNA seen in responding participants in the ABIVAX-004 study and support the continued development of ABX464 as a component of cure eradication strategies 19

20 ABX464: Next Steps ABX second cohort A protocol amendment for the second cohort has been implemented with daily ABX mg over 84 days in order to Assess safety with a lower dose Study the potential decay of the HIV reservoir beyond 28 days Assess the impact of ABX464 on tissue HIV reservoir Top line data available in July 2018 ABX (planned) Evaluate time needed to achieve maximal reduction of HIV reservoir in chronically infected well suppressed HIV patients ABX (planned) Evaluate time needed to achieve maximal reduction of HIV reservoir in early treated well suppressed HIV patients 20

21 ABX study design 21

22 What data should Phase IIB studies provide us What data should 006 / 007 studies Phase IIB studies provide us Can HIV DNA be suppressed to the lowest level possible How long does this take Is the response dependent on HIV reservoir at baseline Is the response dependent on dose ( 50 versus 100 mg ) Do early treated HIV patients have a faster decline Are inflammatory markers ( which??) influenced Is there any evidence of immune reaction leading to long term HIV DNA suppression Is HIV DNA suppression sufficient or are functional assays needed before treatment interruption What % of patients are eligible for treatment interruption Exploratory outcome of treatment interruption 22 22

23 THANK YOU 23